This study will systematically evaluate whether cannabinoids can enhance the analgesic efficacy of opioids, which will advance the use of cannabinoids for the treatment of acute and/or chronic pain. Chronic pain affects over 100 million Americans. Opioids are unanimously recognized as the most effective drugs for the relief of pain and suffering6, but the US is now suffering from an epidemic of abuse, addiction and accidental deaths resulting from the increased sale and use of opioids. There is legitimate value in identifying adjuncts that might reduce reliance on opioids while maintaining adequate pain relief. Preclinical studies report that co- administering cannabinoids with opioid agonists significantly and reliably reduce the amount of opioids required for analgesia but this hypothesis has not been rigorously evaluated in humans. This proposal will conduct 2 independent studies that will evaluate the effects of a different cannabinoid (Study 1: dronabinol, Study 2: nabilone) on opioid-induced analgesia. Each study will enroll 60 healthy adults (30 men/women) to conduct a within-subject, dose-response evaluation of cannabinoids on the analgesic effect of hydromorphone (Dilaudid). Subjects will complete a Qualifying session and 6 experimental sessions that will occur once weekly and will require subjects to admit themselves into the clinical research unit the night before the session to complete the study session. Subjects will receive a dose of hydromorphone (1mg, IM) and a double-blind oral dose of study drug or placebo the morning of each experimental session, and will undergo quantitative sensory testing (QST; a comprehensive pain testing battery), provide self-report ratings of drug effects, and complete a neurocognitive battery. QST testing will comprehensively and systematically measure pain sensitivity, and provide information on the full range of analgesic effects possible across a wide variety of pain measures, including threshold responses (thermal, pressure), temporal summation, cold pressor, conditioned pain modulation, and capsaicin sensitization. Primary outcomes will be magnitude and duration of pain as a function of study drug dose. Additional primary aims include proxy measures of abuse liability and neurocognitive performance. All measures will be assessed as a function of sex, due to substantial evidence that men/women differ with regard to pain perception, endogenous cannabinoid receptor density, and opioid response. We hypothesize that cannabinoids will shift the analgesic curve of hydromorphone and enhance analgesia effects. This will be the 1st human laboratory study to evaluate combinations of cannabinoids and opioids using QST, and results will identify whether a signal for this medication combination exists that should be advanced into randomized controlled trial evaluations with clinical pain populations. This study will also assess aspects that would impact drug development (abuse liability, neurocognitive impairment), as well as the effects of sex and cannabinoid type on outcomes. Results from this study will help advance the acceptance of cannabinoids from use with only treatment-refractory pain conditions to widespread societal use for clinical pain.